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BACKGROUND: This study was designed to determine the recommended dose of carboplatin-pemetrexed in elderly (≥75 years old), chemotherapy-naive patients with advanced nonsquamous nonsmall-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients received escalated doses of carboplatin and pemetrexed every 3 weeks for four cycles. Patients with an objective response and stable disease continued pemetrexed therapy until disease progression or unacceptable toxicity was observed. RESULTS: The combination of carboplatin at an area under the concentration-time curve (AUC) of 5, and 500 mg/m(2) pemetrexed, was determined to be the recommended dose for elderly patients with advanced nonsquamous NSCLC. Of 17 patients, 10 received a median of five cycles of pemetrexed maintenance therapy without unexpected or cumulative toxic effects. The study had an overall response rate of 47.1%. The median progression-free survival time was 142 days (95% confidence interval [CI] 68-216 days) and the median overall survival time was 461 days (95% CI 168-754 days). CONCLUSIONS: This combination was a tolerable and effective regimen, and recommended dose (RD) was carboplatin [area under the curve (AUC) of 5]/pemetrexed (500 mg/m(2)) every 3 weeks, in chemotherapy-naïve, elderly (≥75 years old) patients with advanced nonsquamous NSCLC.

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The effects of a tropical cyclone on the distribution of hatchery-reared black-spot tuskfish Choerodon schoenleinii were examined using acoustic telemetry. Nine fish were released in Urasoko Bay, Ishigaki Island, Japan, in September 2006, and another nine were released in June to July 2007, before a cyclone's passing through the area in September 2007. Data for the fish released in 2006 were used as the cyclone-inexperienced group to compare their distribution pattern to that of the 2007 cyclone-experienced group. Both groups of fish were monitored for up to 150 days. Of the nine fish in each group, four (44%) and two (22%) were monitored for over 150 days in the cyclone-inexperienced and the cyclone-experienced groups, respectively. Three of the five fish that had settled in the monitoring area left the area within a few days of the cyclone event. To estimate the time of disappearance of the fish, maximum wind speed during a period of 7 days (indicating the occurrence and intensity of the tropical cyclone), fish size and release year were evaluated as explanatory variables using a Cox proportional hazards model with Akaike's information criterion. The best predictive model included the effect of maximum wind speed. One fish that left the monitoring area displayed movement patterns related to strong winds, suggesting that wind-associated strong currents swept the fish away. No relationships were found between the movement patterns of the other two fish and any physical environmental data. The daily detection periods of one of the two fish gradually decreased after the cyclone hit, and this fish eventually left the monitoring area within 3 days, suggesting that it shifted to a habitat outside the monitoring area. These results indicate that tropical cyclones have both direct and indirect effects on the distribution of hatchery-reared C. schoenleinii.

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We analyzed the long-term outcomes of 1021 patients with acute lymphoblastic leukemia (ALL), enrolled in four successive clinical trials (ALL811, ALL841, ALL874 and ALL911) between 1981 and 1993. All patients received risk-adopted therapy according to leukocyte count and age at the time of diagnosis. The median follow-up durations of the four studies were 17.8 years in ALL811, 15.5 years in ALL841, 11.9 years in ALL874 and 15.8 years in ALL911. Patients' event-free survival (EFS) and overall survival (OS) rates at 12 years were 41.0 and 54.3% in ALL811, 50.2 and 60.2% in ALL841, 57.3 and 64.7% in ALL874, and 63.4 and 71.7% in ALL911, respectively. Thus, cure can become a reality for about 70% of children with ALL. There is, however, still a significant difference in survival outcomes according to risk group. Late effects were observed in 70 patients out of 834 (8.4%); hepatitis and short stature were most commonly reported. Reduction of late adverse effects for all patients and development of new treatment strategies for very-high-risk patients are major issues for upcoming trials to address.

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Electrochemical treatments are expected to be effective for the coating of calcium phosphate ceramics to a titanium substrate. In the present study, two types of chronoamperometry with a step potential and a cyclic wave potential at low voltage (up to 2.0 V) and low current density were performed in Hanks' solution to modify the surface characteristics of titanium. Titanium oxide film formed by self-passivation, that formed as reconstructed film during electrochemical treatments, and a calcium phosphate layer precipitated through treatments were characterised by X-ray photoelectron spectroscopy. The thickness and compositions of the surface films and layers were quantified from the XPS results. Calcium phosphate formation during immersion in Hanks' solution for 1.0 Ms was evaluated by scanning electron microscopy with energy-dispersive X-ray spectrometry. The results confirmed that the electrolytic treatments in this study were effective to accelerate calcium phosphate formation on titanium in Hanks' solution in spite of their lower voltage than conventional methods. The results also suggested that the hydroxyl group in the surface oxide film might contribute to the formation of calcium phosphate. This technique is a promising process for the treatment of thin titanium materials.

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Dielectric properties of E. coli cell have been re-studied by means of the three-shell spheroidal model, where the three shells correspond to the outer membrane, the periplasmic space and the inner membrane, respectively. With the model, a curve-fitting procedure has been developed to analyze the dielectric spectra. Although E. coli cell has been studied before, its special morphological structure was taken into account more comprehensively than any previous model in the present work. Dielectric properties of various cell components have been estimated from the observed dielectric spectra, especially the permittivity of the outer membrane, which was evaluated quantitatively for the first time. The values of epsilon(om) were 12 for kappa(om) of 0 to 10(-4) S/m and 34 for kappa(om) of 10(-3) S/m. The specific capacitance of the inner membrane was 0.6-0.70 microF/cm(2). The relative permittivity and the conductivity of the cytoplasm were about 100 and 0.22 S/m, respectively, and the conductivity of the periplasmic space was 2.2-3.2 S/m.

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Among 11 JMML children, two had an abnormal karyotype, and nine had a normal karyotype at onset. In one patient with trisomy 8 and four patients with a normal karyotype, a new clone with an aberrant karyotype emerged 1-14 months after 6-mercaptopurine (6-MP) therapy as shown by G-banding analyses. Fluorescence in situ hybridization disclosed that an abnormal clone existed in approximately 3-6% of bone marrow cells at onset or before 6-MP therapy in all the four cases examined, and increased to approximately 12-90% during the treatment. In culture with granulocyte-macrophage colony-stimulating factor, cytogenetically abnormal clones that proliferated during 6-MP therapy possessed significantly less sensitivity to the antimetabolite, compared with cells that decreased in numbers after the therapy. A PTPN11 mutation was detected in all of granulocyte-macrophage colonies irrespective of karyotypic aberration in one patient, whereas approximately 80% of erythroid colonies and 20% of mixed colonies possessed neither a PTPN11 mutation nor chromosomal abnormalities. The appearance of chromosomal aberrations shown by G-banding during 6-MP therapy in some JMML cases may result, in part, from the growth of a 6-MP-refractory clone that already exists at onset. It is possible that treatment with 6-MP promotes progression of the disease.

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The clinical utility of minimal residual disease (MRD) measurements following allogeneic stem cell transplantation (SCT) in childhood ALL is controversial. We therefore performed a multi-institutional study of MRD in bone marrow samples taken before SCT and at 1, 3, 6 and 12 months after SCT. Case-specific clonal rearrangements of IgH and TCR genes and expression levels of Wilms' tumor 1 (WT1) mRNA were determined by PCR or RT-PCR methods. In total, 95 cases met all criteria for analysis of informative IgH/TCR markers and quantitative WT1 mRNA expression levels. During the 2-year (median 414 days) study period, 20 patients relapsed. Although the proportion of patients with a positive IgH/TCR result before SCT was significantly reduced at 1 month after treatment (P<0.001), attesting the efficacy of SCT, serial measurements of IgH/TCR rearrangements did not correlate with leukemic relapse. Clonal switch was demonstrated in 11 of the 14 patients with bone marrow relapse, indicating that the poor predictive power of the MRD assay most likely reflected the loss of PCR targets. WT1 expression was not related to either MRD detection by IgH/TCR assays or to clinical leukemic relapse. The clinical value of serial MRD monitoring would be limited in ALL patients undergoing SCT.

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To evaluate the clinical implications of CD45 expression in acute childhood lymphoblastic leukemia (ALL), we measured the CD45 expression of blast cells from 133 untreated patients with childhood B-precursor ALL (n = 118) or T-ALL (n = 15). CD45 expression (> or = 20%) was detected in all 15 cases (100%) of T-ALL, and 101 cases (86%) of B-precursor ALL. In 122 cases, the fluorescence intensity of the CD45 expression was measured as a relative value; the ratio of average linear values (RALV) of CD45 on the blasts to that on CD3-positive T-lymphocytes from the same specimen. The expression was more intense in the T-ALL cases than in the B-precursor ALL cases (RALV, mean +/- SE: T-ALL 0.230 +/- 0.04 vs. pro-B ALL 0.150 +/- 0.012/pre-B ALL 0.153 +/- 0.019, p < 0.05). However, the intensity of the CD10, CD19, CD20 and CD34 antigen immunoreactivity did not correlate with the CD45 expression. Patients with hyperdiploidy (chromosome number > 50) showed significantly lower levels of CD45 expression than patients with t(1;19) or normal karyotypes (RALV, mean +/- SE: 0.081 +/- 0.022 vs. 0.133 +/- 0.03/0.143 +/- 0.019, p < 0.05). Other clinical features such as age, gender and WBC count did not correlate with CD45 expression. The prognostic implications of CD45 expression were studied in non-high-risk (low-risk + intermediate-risk) (n = 60) and high-risk patients (n = 52) with B-precursor ALL who had been treated with the risk-directed protocol of ALL-941 trial. Although CD45 expression did not correlate with the event-free survival (EFS) of the non-high-risk patients, there was a significant correlation between the expression levels and the EFS of the high-risk patients: the 3-year EFS rate of the CD45low group (n = 26, RALV = 0.017-0.132) was 88 +/- 7% versus the CD45high group (n = 26, RALV = 0.133-0.450) at 34 +/- 24% (p < 0.05). These results show that the levels of expression of the CD45 antigen on leukemic lymphoblasts are significantly correlated with the clinical features and prognosis of childhood ALL.

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Self-disruptive Escherichia coli that produces foreign target protein was developed. E. coli was co-transformed with two vector plasmids, a target gene expression vector and a lysis gene expression vector. The lytic protein was produced after the expression of the target gene, resulting in simplification of the cell disruption process. In this study, the expression of cloned T4 phage gene e or t was used for the disruption of E. coli that produced beta-glucuronidase (GUS) as a model target protein. The expression of gene e did not lead to prompt cell disruption but weakened the cell wall. Resuspension with deionized water facilitated cell lysis, and GUS activity was observed in the resuspended liquid. Expression of gene e at mid logarithmic growth phase was the optimal induction period for GUS production and release. On the other hand, the expression of gene t induced immediate cell lysis, and intracellular GUS was released to the culture medium. Maximum GUS production was obtained when gene t was induced at late logarithmic growth phase.

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Recently, we demonstrated the expression of rhodopsin in the tail fin of the Xenopus tadpole, in which photosensitive melanophores exist (Miyashita et al, The photoreceptor molecules in Xenopus tadpole tail fin, in which melanophores exist. Zool Sci 18:671-674, 2001). The presence of opsin molecules in pigment cells of lower vertebrates raises the possibility that pigment cells in animal skin function as photosensors generally. To explore this possibility in higher vertebrates, we tried to detect photoreception molecules in mammalian melanocytes. We extracted total RNA from Melan a2, a cell line of immortal murine melanocyte, which is derived from C57BL mice. The DNA sequence obtained by reverse transcriptase-polymerase chain reaction (RT-PCR) amplification was homologous to the corresponding portion of the sequence of ocular rhodopsin of mice. Western blotting and fluorescent immunocytochemistry showed the existence of the opsin protein in the melanocytes. Another cell line, EL4, which is derived from lymphoma of C57BL/6N, scarcely expresses opsin mRNA, as judged by RT-PCR. Thus expression of the opsin gene is not ubiquitous among immortal cell lines. Detection of rhodopsin mRNA in murine tissues of C57BL/6N by RT-PCR showed its presence in the eye and skin but not in the liver. The role of the opsin molecule in melanocyte is not known at present, but this will provide additional insight into photoreception systems in animal skin.

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Dielectric spectroscopy has been used to monitor the early embryogenesis of frog (Xenopus laevis) eggs. The dielectric spectra of a single egg in suspension over the frequency range 10 Hz to 10 MHz were collected at various stages of its development. The uncleaved egg showed a dielectric dispersion with a narrow distribution of relaxation times. After the first cleavage, the dielectric spectra were mainly composed of two subdispersions. In the cleavage process, up to the morula stage, changes in the spectra were quantitatively simulated by the 'cell-aggregate' model in which the embryo is regarded as a concentrated suspension of shell-spheres that correspond to the blastomeres (i.e. the cells within the embryo). In the stages from the morula to the blastula, the changes in the dielectric spectra were explained as due to a reduction in the size of the blastomere accompanied by an expansion of the blastocoel (i.e. the central cavity in the embryo) using the 'vesicle-inclusion' model that is a cell aggregate covered with a less conducting shell corresponding to the outermost layer of tightly interconnected cells.

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To address the issue of salvageability in relapsed children with NHL who had all received the same frontline therapy, we retrospectively studied the treatment response and the outcome of 27 children who relapsed following the CCLSG-NHL890 protocol. The reinduction rates and 3-year survival rates (mean +/- SD) were as follows: lymphoblastic lymphoma (LB, n = 9), 44% & 17 +/- 14%; leukemia lymphoma syndrome (LLS, n = 8), 25% & 0%; large cell lymphoma (LC, n = 3) 100% & 67 +/- 27%; Burkitt's lymphoma (B, n = 7) 0% & 0%. Thus, the salvageability of LC lymphoma was good, but the outcome of Burkitt's lymphoma was very poor. CCLSG-NHL960 protocol for LB lymphomas and intensive multiagent regimens for LC lymphomas produced favorable response rates, but the effect of the high-dose Ara-C regimen for Burkitt's lymphoma was not determined. The initial stages of the disease seemed to be associated with the patient outcome: the outcome of the patients in stage IV was inferior to that of patients in stages II or III. Other clinical variables, such as relapse sites, relapse time and BM rescue did not affect the patients' outcome.

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A dielectric method has already been developed for the real-time monitoring of cell cycle progression in synchronized cell culture (Asami et al., 1999). This method, in combination with DNA content analysis by fluorescence-activated cell sorting (FACS), was applied to the synchronized cell culture of a CDC28-13th mutant (Saccharomyces cerevisiae). In synchronous cell growth, relative permittivity epsilon (or dielectric constant) for the culture broth showed cyclic changes at low frequencies below 0.5 MHz, being correlated to phases in the cell cycle that were simultaneously determined by FACS. The epsilon increased in the period from S phase to G(2) phase and decreased between M and G(1) phases. Peaks in these cyclic changes of epsilon indicated the time when daughter cells segregated from mother cells.

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In sea urchin embryos, the rate of respiration, as a result of electron transport through the mitochondrial respiratory chain, was enhanced after hatching without any change in the intrinsic capacity of electron transport in mitochondria. The increase in respiratory rate after hatching was accompanied by an evident decrease in intracellular adenosine triphosphate (ATP) concentration without any change in intracellular levels of adenosine diphosphate (ADP) and adenosine monophosphate (AMP). Adenosine triphosphate is proposed to fortify acceptor control of respiration at high concentrations and to reduce the respiratory rate even in the presence of ADP, the acceptor. The relationships between the respiratory rate and intracellular ATP concentration in embryos were the same as those in mitochondria isolated from embryos, obtained in the presence of ADP at the same concentration as in the embryos. Probably, the respiratory rate is enhanced after hatching because of the decrease in the level of ATP. In embryos kept in a medium containing adenosine, intracellular ATP concentration increased especially after hatching, without any change in the ADP level, and the respiratory rate after hatching was made as low as the rate expected, based on the relationships obtained on isolated mitochondria. The respiratory rate in embryos probably depends on intracellular ATP concentration, irrespective of the developmental stage in early development.

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This study was designed to evaluate the utility of blasts with a clear halo around their nucleoli (BCHN) as a predictive indicator of disease progression in myelodysplastic syndromes (MDSs) and aplastic anemia (AA). Bone marrow aspirates from 75 patients with MDSs and 18 with AA were fixed in 95% ethanol solution or 10% neutral formalin and stained with the Papanicolaou method. BCHNs were detected in 57 of 75 patients with MDSs and in 10 of 18 AA patients. Disease progression was restrictedly observed in 17 patients with MDSs who had BCHNs at onset and in 1 patient with AA. The proportion of BCHNs increased with disease progression in these 16 of 17 patients with MDSs. The presence of BCHNs at onset and the increase in proportion of BCHNs during the clinical course of MDSs were significant indications for predicting disease progression.

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In hemophagocytic lymphohistiocytosis (HLH), cytokine-induced pancytopenia is a common finding and is associated with hypoplastic and hypocellular bone marrow and abundant hemophagocytosis. To date, neutrophil nuclear segmentation abnormalities have not been clarified in HLH patients. We report a study of bone marrow from 6 cases of HLH that showed abnormal granulocytes, dyserythropoietic changes, and micromegakaryocytes mimicking the findings in myelodysplasia at the onset of disease. Pelger-Huët anomalies were particularly noted in all cases. The increased levels of cytokines in these cases may have caused cellular damage leading to the morphological changes in the bone marrow of these HLH patients. The impact of these findings on pathophysiology and prognosis in HLH patients remains to be determined.

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Infection of Escherichia coli cells by T4 phage at a multiplicity of infection (MOI) of 0.01 caused inhibition of cell lysis for up to 4 h. Such cells grown under aerobic condition were lysed by external stimuli such as cold shock, osmotic shock or addition of toxic substances, e.g., carbonyl cyanide m-chlorophenylhydrazone (CCCP). However, the effects of these external stimuli were reduced by transferring the cells to static incubation, by which dissolved oxygen was consumed by the cells within 10 min. The cells became insensitive to such external stimuli when the culture was deoxygenated with nitrogen gas. Following infection with a lysozyme amber mutant, eL1a, the cell membrane permeability was found to be increased either by cold shock or osmotic shock treatment of cells grown under aerobic conditions, but not in cells transferred to the static incubation. Oxygen limitation was suggested to enhance membrane stability in relation to cell lysis following the cold or osmotic shock treatment.

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Standard treatment for renal cell carcinoma (RCC) is radical nephrectomy with lymph node dissection. Stages I and II have encouraging prognoses, but Stage III with regional lymph node metastasis can be unfavorable. Adjuvant therapy for pediatric patients with advanced RCC with lymph node involvement or metastatic lesion has not been defined. Advanced pediatric RCC is reported in two patients (boys, aged 6 and 9 years: Stage IIIs, Robson; Stage III and IV, pTNM classification) treated by nephrectomy and lymph node dissection followed by postoperative interferon-alpha (IFN), that can be used as an adjuvant therapy with side effects such as fever, bone marrow suppression, or decreased liver function. One is doing well for 7 years, another is suffered from lung metastases at 3 years after surgery. Although immunotherapy is expected to improve survival in pediatric patients with advanced RCC, surgical resection of renal and metastatic tumors remains the standard treatment.

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